Coarse-grained molecular simulations of allosteric cooperativity
| Autor: | John J. Portman, Prithviraj Nandigrami |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Calmodulin genetic structures Binding energy Population Allosteric regulation Molecular Conformation General Physics and Astronomy FOS: Physical sciences Cooperativity Ligands 03 medical and health sciences Allosteric Regulation Computer Simulation Physics - Biological Physics Physical and Theoretical Chemistry Binding site education Conformational ensembles education.field_of_study biology Chemistry Biomolecules (q-bio.BM) Ligand (biochemistry) 030104 developmental biology Quantitative Biology - Biomolecules Biological Physics (physics.bio-ph) FOS: Biological sciences biology.protein Biophysics Calcium Monte Carlo Method Protein Binding |
| Zdroj: | The Journal of chemical physics. 144(10) |
| ISSN: | 1089-7690 |
| Popis: | Interactions between a protein and a ligand are often accompanied by a redistribution of the population of thermally accessible conformations. This dynamic response of the protein's functional energy landscape enables a protein to modulate binding affinities and control binding sensitivity to ligand concentration. In this paper, we investigate the structural origins of binding affinity and allosteric cooperativity of binding two calcium ions to each domain of calmodulin (CaM) through simulations of a simple coarse-grained model. In this model, the protein's conformational transitions between open and closed conformational ensembles are simulated explicitly and ligand binding and unbinding is treated implicitly within the Grand Canonical Ensemble. Ligand binding is cooperative because the binding sites are coupled through a shift in the dominant conformational ensemble upon binding. The classic Monod-Wyman-Changeux model of allostery with appropriate binding free energy to the open and closed ensembles accurately describes the simulated binding thermodynamics. The simulations predict that the two domains of CaM have distinct binding affinity and cooperativity. In particular, C-terminal domain binds calcium with higher affinity and greater cooperativity than the N-terminal domain. From a structural point of view, the affinity of an individual binding loop depends sensitively on the loop's structural compatibility with the ligand in the bound ensemble, as well as the conformational flexibility of the binding site in the unbound ensemble. Comment: 8 pages, 6 figures; supplemental information: 2 pages, 2 figures |
| Databáze: | OpenAIRE |
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